Clearance of senescent macrophages ameliorates tumorigenesis in KRAS-driven lung cancer

The accumulation of senescent cells in the tumor microenvironment can drive tumorigenesis in a paracrine manner through the senescence-associated secretory phenotype (SASP). Using a new p16-FDR mouse line, we show that macrophages and endothelial cells are the predominant senescent cell types in murine KRAS-driven lung tumors. Through single cell transcriptomics, we identify a population of tumor-associated macrophages that express a unique array of pro-tumorigenic SASP factors and surface proteins and are also present in normal aged lungs. Genetic or senolytic ablation of senescent cells, or macrophage depletion, result in a significant decrease in tumor burden and increased survival in KRAS-driven lung cancer models. Moreover, we reveal the presence of macrophages with senescent features in human lung pre-malignant lesions, but not in adenocarcinomas. Taken together, our results have uncovered the important role of senescent macrophages in the initiation and progression of lung cancer, highlighting potential therapeutic avenues and cancer preventative strategies. [Display omitted] For a Figure360 author presentation of this figure, see https://doi.org/10.1016/j.ccell.2023.05.004. •The p16-FDR mouse model can be used to isolate, trace, and ablate senescent cells•Senescent macrophages in lung tumors and naturally aged lungs are molecularly similar•Senescent macrophage ablation decreases tumor burden by promoting immunosurveillance•Human pre-malignant lung tumors contain macrophages expressing senescent markers Haston et al. identify a population of senescent macrophages with pro-tumorigenic activities in KRAS-driven murine models of lung adenocarcinoma, which show a unique molecular signature that is conserved in the non-tumorigenic, normal aged lung. They also uncover the presence of macrophages expressing senescent markers in human pre-malignant lung tumors.